The preservation of biopharmaceutical materials is essential in the manufacture and storage of these productions. One traditional method used to preserve these pharmaceutical materials is through freezing, also known as cryopreservation.
Biopharmaceutical materials are often frozen and thawed throughout the manufacturing process, as well as afterwards, such as during shipping. Freezing these materials reduces the chances of degradation, microbial contamination and denaturing that can occur at room temperature. For example, cryopreservation allows materials to be partially prepared, and then stored in an intermediate condition, thus decoupling the various activities involved in the manufacture of the product. In order to do so, they are often placed in storage containers, often referred to as biocontainers, ranging in size from a few milliliters to thousands of liters. In some instances, the biocontainers are made from a plastic material with a fixed form. Other biocontainers are more flexible and can take on a multitude of forms. In certain instances, these biocontainers are placed within frames, carriers or other structures that define their shape.
However, in order for cryopreservation to be successful, careful attention must be paid to the operating parameters. It has been reported that the rate at which biopharmaceutical materials are frozen is critical to their continued utility. For example, if the material is frozen too slowly, the diffusion of solutes in liquid bulk is exacerbated, leading to potential issues such as a pH shift, increased ionic strength, and phase separation. In addition, problems such as the formation of small ice crystals within the biopharmaceutical material, e.g., within a protein structure, can stress the material causing, for example, denaturation of the protein. Denaturation is often indicated by unfolding of the protein, thereby causing it to lose its efficacy, and potentially aggregating.
Within a bulk sample, denaturation of material can occur non-uniformly due to non-uniformities in the heat cycles. For instance, a frozen sample exposed to an instantaneous heat source during transport can cause the outer surface to melt. Ideally, a uniform freeze rate across the sample would reduce local denaturation as molecules within the interface layer may experience excessive shear.
To attempt to mitigate several of these issues, custom freezers have been developed, e.g., where the freezer has one or more temperature sensors that are an integral part of the freezer. These integral temperature sensors are either placed inside the biocontainer or positioned such that they abut the biopharmaceutical container, thereby allowing them to record the temperature of the contents of the biocontainer. Based on the measured reading of such a sensor, the freezer adjusts its operating parameters, either attempting to cool more quickly or to maintain the temperature.
While such freezers may be useful in proper cryopreservation, there are many drawbacks. For example, the user is forced to buy a complete system in order to receive the benefits. In addition, the capacity of the freezer may be limited, or the number of temperature sensors may be limited. In other words, while one biocontainer may have a temperature sensor to monitor its temperature profile during the freezing process, other biocontainers within the same freezer may not be properly monitored. This can be problematic as the temperature profile varies within the freezer enclosure. For example, a biocontainer near the door may experience condensation thereby creating different heat conduction pathways. Biocontainers located near the interior walls may freeze more quickly. Furthermore, these freezers only monitor the temperature of the biopharmaceutical material while in the freezer. Any variations in temperature experienced during transit or during the thawing process are not monitored.
Therefore, there exists a need for a low cost, simple solution that enables the user to monitor the temperature profile of each biopharmaceutical container during the cryogenic process, so as to insure the integrity of each biocontainer. Furthermore, a method of monitoring the temperature during the thawing process and during transit would be advantageous.